In recent years, the increasing incidences of metabolic diseases including obesity, diabetes, dyslipidemia, hypertension, and atherosclerosis, have led to higher risks of heart diseases, a leading cause of mortality worldwide. The healthcare cost associated with treatment is putting major burdens on the healthcare systems of developed as well as developing countries. Therefore, identifying novel targets and pharmacologic agents to treat and/or prevent these disorders are of high priorities.
Both type 1 (insulin-dependent diabetes mellitus, IDDM) and type 2 (noninsulin-dependent diabetes mellitus, NIDDM) diabetes are characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state or after administration of glucose during an oral glucose tolerance test. Insulin is the hormone that regulates glucose utilization by stimulating glucose and lipid metabolism in the main insulin-sensitive tissues including muscle, liver and adipose tissues. Inappropriate regulation of energy metabolism in these tissues accounts for most of the alterations in glucose homeostasis seen in patients with type 2 diabetes. In addition, patients having type 2 diabetes often have hyperinsulinemia (elevated plasma insulin levels). Insulin resistance, which means a resistance to the effect of insulin, plays an early role in the pathogenesis of type 2 diabetes.
Skeletal muscle and liver are both key insulin-responsive organs responsible for maintaining normal glucose homeostasis. Mitochondrial dysfunction has been closely associated with skeletal muscle insulin resistance in several studies. In skeletal muscle of human type II diabetics, the expression levels of mitochondrial oxidative phosphorylation (OXPHOS) genes are reduced. The OXPHOS genes that are dysregulated in type II diabetic patients are under the transcriptional control of peroxisome proliferator-activated receptor □ coactivator-1□ (PGC-1α). The reduction of PGC-1α level will in theory induce the reduction of the OXPHOS genes and reduce the oxidation of fatty acids, and thus result in the reducing of lipid deposition in the skeletal muscle, and finally induce insulin resistance and type II diabetes. Actually, the imbalance of PGC-1α is a common phenomenon of pre-diabetics. This further proves that the reduction of PGC-1α level is an important factor inducing the diabetes.
Estrogen-related receptors (ERRs) are a kind of nuclear hormone receptor closely related to the estrogen receptor α. During the binding of the ERRs and their co-activator, no exogenous ligands and endogenous ligands participate, which is considered to construct constitutively active orphan nuclear hormone receptors. Studies show that ERRs include 3 kinds of different subtypes, i.e. ERRα, ERRβ and ERRγ (related documents: Giguere, V., Nature, 1988, 331, 91˜94; Hong, H J. Biol. Chem. 1999, 274, 22618-22626; Heard, D. J. Mol. Endocrinol. 2000, 14, 382-392; Giguere, V. T. Trends. Endcrinol. Metab. 2002, 13(5), 220-225; etc.). ERRβ mainly relates to the upgrowth of organisms, and its expression is strictly controlled after birth, and there is a small amount of expression in the liver, stomach, skeletal muscle, heart and kidney. The expression of ERRγ mainly lies in the spinal cord and the centra nervous system. ERRα mainly exists in metabolically active tissues or organs such as skeletal muscle, heart, kidney and adipose tissue (related documents: Giguere, V., Nature, 1988, 331, 91˜94; Sladek, R. Mol. Cell. Biol. 1997, 17, 5400˜5409; etc.), and the interaction of ERRα and PGC-1 (peroxisome proliferator activated receptor γ (PPAR-γ) coactivator 1) controls the transcription of mitochondrial oxidative phosphorylation (OXPHOS) genes and regulates the material and energy metabolism of glucose and adipose (related documents: Schreiber, S. N. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 6472˜6477; Schreiber, S. N. J. Biol. Chem. 2003, 278, 9013˜9018; Huss, J. M. J. Biol. Chem. 2002, 277, 40265-40274; Ichida, M.; Nemoto, S. J. Biol. Chem. 2002, 277, 50991-50995; etc.).
The OXPHOS is the most crucial step during the ATP energy generating by material metabolism of the glucose, adipose, etc. PGC-1 is an important regulator of the OXPHOS and plays an important regulation role during the heat generation in the tissues such as skeletal muscle and brown adipose, and respiration and mitochondrial biogenesis in the muscle cell, and the transition of skeletal muscle fiber. Furthermore, PGC-1 also controls the expression of genes for encoding many kinds of gluconeogenic enzymes (related documents: Mootha, V. K. Nat. Genet. 2003, 34, 267-273; Patti, M. E. Proc. Natl. Acad. Sci. USA 2003, 100, 8466-8471; Puigserver, P. Endocr. Rev. 2003, 24, 78-90). Studies show that the reduction of PGC-1 may affect the metabolism of energy materials such as glucose and adipose, and induce excess blood glucose and lipid deposition in the skeletal muscle, and finally induce insulin resistance and type II diabetes.
ERRα is the direct downstream target gene of PGC-1α. The direct interaction of ERRα and PGC-1α controls the transcription of genes such as OXPHOS and fatty acid oxidase so as to regulate the process of OXPHOS (Mootha, V. K. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 6570-6575). Studies show that under the stimulation of environment signals such as fasting, physical training and cold, PGC-1α may facilitate the expression of ERRα, and further facilitate the transcription of ERRα by way of binding with ERRα to induce ERRα to bind with the specific binding site of gene promoter of itself. The interaction between the PGC-1α and ERRα can further promote the binding of ERRα with the other downstream gene promoters of PGC-1α, and facilitate the transcription of these downstream functional genes (such as phosphoenolpyruvate carboxykinase (PEPCK), medium chain acyl dehydrogenase (MCAD), and pyruvate dehydrogenase kinase 4 (PDK4)), and thus control the OXPHOS and the fatty acid oxidation effectively and promote the metabolism of fatty acid and glucose (FIG. 1A) (related documents: Schreiber, S. N. et al. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 6472˜6477. Willy, P. J.; et al, Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 8912˜8917, etc.)
Therefore, with small molecular compounds especially small molecular promoter ERRα regulates the function of ERRα and PGC-1α, the function of OXPHOS genes is effectively improved, the oxidization of fatty acid is facilitated or the utilization of glucose is reduced, and it can be used as an effective way to cure diabetes and the related obesity, hyperglycemia, low blood glucose tolerance, insulin resistance, hyperlipidemia, lipid disorders, high blood cholesterol, high triglyceride, hypercholesteraemia, low high-density lipoprotein cholesterol levels, high low-density lipoprotein level, atherosclerosis, and its secondary disease, narrow blood vessels, abdominal obesity, metabolic syndrome and fatty liver. Furthermore, since the small molecular promoter ERRα can improve the expression of PGC-1α gene and increase the sensitivity of insulin. Therefore, they can also be used with other insulin sensitizer or insulin secretagogues to improve the clinical effect.
In addition, reduction of estrogen levels in post-menopausal results in an increase of bone loss leading to osteoporosis. Over-expression of ERRα in osteoblasts increases bone nodule formation, while reducing the expression by anti-sense results in a decrease of bone nodule formation. Therefore, compounds that enhance the activity of estrogen related receptors (ERRα, β, and γ, etc.) activity may have an anabolic effect for the regeneration of bone density. Conversely, with respect to bone diseases that are a result of abnormal bone growth, compounds that will interact with estrogen related receptors (ERRα, β, and γ) and decrease its biological activity may provide a benefit for the treatment of these diseases by retarding bone growth.
Although estrogen related receptors alpha, beta and gamma (ERRα, ERRβ and ERRγ) are considered to be orphan nuclear hormone receptors that display constitutively active transcriptional activities, synthetic phenolic acyl hydrazones have recently been demonstrated to be selective ERRβ and ERRγ agonists through binding to the C-terminally located ligand binding domain (LBD) and activating its function. However, no definitive ERR α agonist has been identified so far that would improve insulin resistance through enhancing the function of PGC1.